Oxidative Stress and Circulating Nuclear DNA (cfDNA) in Acute Kidney Injury and Continuous Renal Replacement Therapies.

October 16, 2024 updated by: Fernando Sanchez

Oxidative Stress and Circulating Nuclear DNA (cfDNA) in Acute Kidney Injury and Continuous Renal Replacement Therapies. Effect of Two Anticoagulation Strategies of the Extracorporeal Purification System in Renal Function Recovery.

Acute kidney injury (AKI) is the inability of the kidneys to perform their functions of purifying and cleaning the blood. It is a frequent complication in hospitalized patients, especially in those admitted to the ICUs. In these situations is common to use machines to artificially and temporarily replace renal function so waste products that can be toxic are removed from the body.

The purpose of this study is to assess the effectiveness and safety of two anticoagulation strategies of the extracorporeal purification system in critically ill patients with acute kidney injury treated with continuous renal replacement therapy (CRRT) evaluating the effect of both strategies in oxidative stress and extracellular nucleosomes and its influence on the recovery of renal function.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Acute kidney injury (AKI) is defined as a sudden deterioration of renal function that causes loss of electrolyte control, acid base status and fluid balance, with subsequent accumulation of nitrogenous waste products that should be eliminated by the kidney. It is a frequent complication in hospitalized patients, especially those admitted to Intensive Care Units (ICUs). Its etiology is usually multifactorial, usually in the context of multiorgan dysfunction syndrome (MODS). The epidemiology and risk factors associated with its development, as well as the type of treatment that these patients are currently undergoing, continues to be the subject of debate, given the impact it has on morbidity and mortality.

To temporary substitute renal function in critically ill patients continuous renal replacement therapies (CRRT) are frequently used. The classification and nomenclature of techniques depends on the duration, continuity and operational characteristics of the treatment system. Thus, we distinguish between continuous techniques and intermittent techniques. Peritoneal dialysis (PD) is rarely used in developed countries for the treatment of AKI in ICU. Intermittent hemodialysis (IHD) is the most frequently used technique, although its use in ICU has considerable limitations on fluid balance, uremia control and elimination of medium molecular weight molecules.

Due to the enormous difficulty of obtaining studies with the necessary statistical power to provide the degree of evidence needed to clarify questions regarding the indications, modalities and other technical aspects of the CRRT, it is commonly used the experience that both the clinical practice in chronic patients as the results of scientific research that intermittent techniques (IHD fundamentally) confers to the clinician.

In patients with IHD, certain conditions are associated with a worse prognosis and an increased risk of mortality. These can include cardiovascular diseases, diabetes mellitus (DM), atherosclerosis, infectious processes, malnutrition, inflammation, oxidative stress, iron deficiency, anemia, calcification, uremia and volume overload. AKI requiring a renal replacement technique (RRT) represents an independent risk factor for mortality in critically ill patients. Oxidative stress and inflammation play important roles in the initiation and extension phases of AKI, as well as in causing injury to distant organs after AKI.

In CRRT to prevent coagulation of the extracorporeal system requires the use of some method of anticoagulation. The most frequent anticoagulation strategies include systemic heparin and regional citrate administration. However, some undesirable effects of CRRT may affect the patient's outcome, including the risks of systemic bleeding and membrane biocompatibility induced by anticoagulants.

Heparin, the most widely used anticoagulant in these techniques, is considered the standard of treatment, however it is contraindicated in patients with a high hemorrhagic risk or in heparin-induced thrombocytopenia.

Regional citrate anticoagulation (RCA), in which only the extracorporeal circuit is anticoagulated by the chelating action of calcium by citrate, is a safe and effective alternative in these cases. RCA has also been described as superior to heparin in terms of biocompatibility, since heparin, in comparison with citrate, can activate the complement and induce neutrophil degranulation in the filter and activate the release of myeloperoxidase (MPO) from the endothelium. The use of citrate, in addition to providing greater biocompatibility and a similar or longer filter duration, could also be associated with less inflammation and possibly with a better survival compared to heparin use, and probably also with a better renal recovery.

Apoptosis is probably implicated as a pathophysiological mechanism in organ injury in the setting of sepsis and systemic inflammatory response syndrome.

The sum effect of the numerous risk factors present in critical patients with AKI treated with CRRT is cumulative, additive, interrelated, complex and often unexpected or completely unknown. Survival in patients with AKI requiring replacement therapy is lower than in other patient populations. At present the accuracy of prediction of mortality and morbidity depending on available biomarkers or clinical condition is not optimal to properly describe and stratify patients properly. The combination of several markers of simultaneous biochemical processes can help to better stratify patients, identify the best therapeutic targets, evaluate the response to different therapies and establish functional prognoses. The usefulness of a parameter that evaluates tissue damage with markers of specific biochemical processes could be considered.

The present randomized, controlled, parallel-group, single centre study aims to evaluate the biocompatibility of two strategies of anticoagulation of the extracorporeal system (RCA and heparin) by using markers of inflammation, oxidative stress and cellular damage and its repercussion in the recovery of renal function. In this setting it would be possible to establish functional prognoses in terms of renal function recovery and to better identify which strategy is most beneficial for each group of patients.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
    • Castellon
      • Castellón De La Plana, Castellon, Spain, 12004
        • Fernando Sánchez

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Adult intensive care patients (age > 18) admitted to the ICU with AKI requiring treatment with continuous renal replacement technique.
  • Patients able to accept being included in the study by signing the Informed Consent (IC). If the patient can not give consent, family consent is requested and, by default, the opinion of the person of trust or designated decision, if present. If there is no family present, trusted person or legal representative designated, the possibility of deferred consent is not contemplated. In this case the patient will not be included in the study.

Exclusion Criteria:

  • Age under 18 years old.
  • Pregnancy and/or lactation.
  • Terminal diseases or life expectancy lower than 48 hours.
  • Increased risk of bleeding (defined as platelet count less than 40x109 / L, partial thromboplastin time (TTPA) over 60 seconds, prothrombin time (PT)international normalized ratio (INR) greater than 2.0 or recent major bleeding).
  • Need of systemic anticoagulation therapy.
  • Contraindication for heparin.
  • Heparin-induced Thrombocytopenia (HIT).
  • Dialysis in the 24 hours prior to inclusion.
  • Hypercalcemia (> 3 mmol / L).
  • Severe Hepatitis: glutamic oxaloacetic transaminase (GOT) or glutamic pyruvic transaminase (GPT) > 1000 IU / L.
  • Cirrhosis.
  • Inclusion in another research protocol.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Heparin

Central venous access will be achieved with a 13 Fr double lumen catheter placed into the internal jugular or femoral vein.

The patient will be connected to the Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany) pump-assisted circuit with a high-flux synthetic membrane. In the heparin arm the anticoagulation technique to be used will be non-fractional heparin.

Blood and ultrafiltrate samples will be taken from the prefilter (inlet filter plasma concentration [Ci]) and postfilter (outlet filter plasma concentration [Co]) sites of the extracorporeal circulation circuit at different times.
Procedure: Central venous access
Venous access will be achieved with a 13 Fr double lumen catheter into the internal jugular or femoral vein.
Device: Pump-assisted circuit
The pump-assisted circuit to be used will be Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany). EMIC2® Fresenius Medical Care high-flux synthetic membrane will be used
Other Names:
  • CRRT
  • Continuous renal replacement therapy
Drug: Heparin sodium
Non-fractional heparin will be used in one arm with an initial dose of 500-1000 IU/hour with adaptation of the infusion to the patient and the clotting time.
Other Names:
  • Heparin
  • Non-fractional heparin
Procedure: Blood and ultrafiltrate samples

Blood samples will be taken from the prefilter (inlet filter plasma concentration [Ci]) and postfilter (outlet filter plasma concentration [Co]) sites of the extracorporeal circulation circuit. The ultrafiltrate will be collected directly from the outlet of the hemofilter (ultrafiltrate concentration [Cuf]).

The samples will taken at the beginning of CRRT (T0) and at the following times: T0, Ci; after 60 min (T1) and after 24 hours (T2) of CRRT, Ci, Co and Cuf.

Venous access will be achieved with a 13 Fr double lumen catheter into the internal jugular or femoral vein.
Experimental: Citrate

Central venous access will be achieved with a 13 Fr double lumen catheter placed into the internal jugular or femoral vein.

The patient will be connected to the Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany) pump-assisted circuit with a high-flux synthetic membrane. In the citrate arm regional citrate anticoagulation of the extracorporeal purification system will be used to avoid coagulation of the circuit.

Blood and ultrafiltrate samples will be taken from the prefilter (inlet filter plasma concentration [Ci]) and postfilter (outlet filter plasma concentration [Co]) sites of the extracorporeal circulation circuit at different times.
Procedure: Central venous access
Venous access will be achieved with a 13 Fr double lumen catheter into the internal jugular or femoral vein.
Device: Pump-assisted circuit
The pump-assisted circuit to be used will be Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany). EMIC2® Fresenius Medical Care high-flux synthetic membrane will be used
Other Names:
  • CRRT
  • Continuous renal replacement therapy
Procedure: Blood and ultrafiltrate samples

Blood samples will be taken from the prefilter (inlet filter plasma concentration [Ci]) and postfilter (outlet filter plasma concentration [Co]) sites of the extracorporeal circulation circuit. The ultrafiltrate will be collected directly from the outlet of the hemofilter (ultrafiltrate concentration [Cuf]).

The samples will taken at the beginning of CRRT (T0) and at the following times: T0, Ci; after 60 min (T1) and after 24 hours (T2) of CRRT, Ci, Co and Cuf.

Venous access will be achieved with a 13 Fr double lumen catheter into the internal jugular or femoral vein.

Other: Regional citrate anticoagulation
Regional citrate anticoagulation will be used in the other arm with an initial dose of 3 mmol/L and with a calcium reinfusion solution at an initial dose of 2 mmol/L, with adaptation of both infusions to the patient ionic calcium levels.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recovery of renal function
Time Frame: Through study completion, an average of 20 days.
Impact of circulating nuclear DNA (cfDNA) and oxidative stress on duration of renal replacement therapy (RRT) in ICU.
Through study completion, an average of 20 days.
Recovery of renal function
Time Frame: Through study completion, an average of 20 days.
Impact of circulating nuclear DNA (cfDNA) and oxidative stress on change of Creatinine from baseline to ICU discharge.
Through study completion, an average of 20 days.
Recovery of renal function
Time Frame: Through study completion, an average of 20 days.
Impact of circulating nuclear DNA (cfDNA) and oxidative stress on change of Creatinine from baseline to hospital discharge.
Through study completion, an average of 20 days.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Activation and elimination of free radicals
Time Frame: 24 hours
Changes in plasma concentration of glutathione (GSH) from baseline (before the initiation of the therapy) to 24 hours after de initiation of the therapy.
24 hours
Activation and elimination of free radicals
Time Frame: 24 hours
Changes in plasma concentration of glutathione disulfide (GSSG) from baseline (before the initiation of the therapy) to 24 hours after de initiation of the therapy.
24 hours
Activation and elimination of biomarkers of inflammation
Time Frame: 24 hours
Changes in plasma concentration of mieloperoxidase (MPO) from baseline (before the initiation of the therapy) to 24 hours after de initiation of the therapy.
24 hours
Activation and elimination of biomarkers of inflammation
Time Frame: 24 hours
Changes in plasma concentration of c-reactive protein (CRP) from baseline (before the initiation of the therapy) to 24 hours after de initiation of the therapy.
24 hours
Activation and elimination of biomarkers of cell damage
Time Frame: 24 hours
Changes in plasma concentration of circulating nuclear DNA (cfDNA) from baseline (before the initiation of the therapy) to 24 hours after de initiation of the therapy.
24 hours
Mass transfer and clearance of free radicals
Time Frame: 24 hours
Changes in plasma concentration of glutathione (GSH) from before to after the passage of blood through the filter
24 hours
Mass transfer and clearance of free radicals
Time Frame: 24 hours
Changes in plasma concentration of glutathione disulfide (GSSG) from before to after the passage of blood through the filter
24 hours
Mass transfer and clearance of biomarkers of inflammation
Time Frame: 24 hours
Changes in plasma concentration of mieloperoxidase (MPO) from before to after the passage of blood through the filter
24 hours
Mass transfer and clearance of biomarkers of inflammation
Time Frame: 24 hours
Changes in plasma concentration of c-reactive protein (CRP) from before to after the passage of blood through the filter
24 hours
Mass transfer and clearance of biomarkers of cell damage
Time Frame: 24 hours
Changes in plasma concentration of circulating nuclear DNA (cfDNA) from before to after the passage of blood through the filter
24 hours
Length of stay
Time Frame: From ICU admission until the date of ICU discharge or date of death from any cause, whichever came first, assessed up to 90 days
Length of stay in ICU
From ICU admission until the date of ICU discharge or date of death from any cause, whichever came first, assessed up to 90 days
Length of stay
Time Frame: From hospital admission until the date of documented hospital discharge or date of death from any cause, whichever came first, assessed up to 90 days
Length of stay in hospital
From hospital admission until the date of documented hospital discharge or date of death from any cause, whichever came first, assessed up to 90 days
Mortality
Time Frame: Through study completion, an average of 20 days.
ICU mortality
Through study completion, an average of 20 days.
Mortality
Time Frame: Day 90 after ICU admission
Hospital mortality
Day 90 after ICU admission

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fernando Sanchez

Collaborators

Hospital General Universitario de Castellón
Hospital Universitario de la Plana

Investigators

  • Study Chair: Fernando Sanchez, MD, La Plana Health Department. Valencian Health Counseling
  • Study Director: Fernando Sanchez, MD, La Plana Health Department. Valencian Health Counseling
  • Principal Investigator: Fernando Sanchez, MD, La Plana Health Department. Valencian Health Counseling

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 9, 2018

Primary Completion (Actual)

April 30, 2021

Study Completion (Actual)

April 30, 2021

Study Registration Dates

First Submitted

July 31, 2018

First Submitted That Met QC Criteria

October 15, 2024

First Posted (Actual)

October 17, 2024

Study Record Updates

Last Update Posted (Actual)

October 18, 2024

Last Update Submitted That Met QC Criteria

October 16, 2024

Last Verified

October 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FER-CIT-2016-01
  • 2016-004361-12 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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